Identification and Characterization of Asymmetrically-Expressed Genes

不对称表达基因的鉴定和表征

• 批准号: 8497720
• 负责人: DANIEL H GESCHWIND
• 金额: $ 57.21万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-10 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8497720
• 关键词: Adult; Animal Model; Autistic Disorder; Award; Behavior; Biological Process; Brain; Cell Adhesion Molecules; Cerebral cortex; Cognition; Cognitive; Complex; Critical Pathways; Development; Disease; Evolution; Gene Expression; Gene Expression Profile; Genes; Homologous Gene; Human; In Situ Hybridization; Language; Methods; Mus; Neurodevelopmental Disorder; Pattern; Proteins; Reverse Transcriptase Polymerase Chain Reaction; Role; Schizophrenia; Speech; Structure; Testing; Work; cognitive function; digital; extracellular; follow-up; gene conservation; insight; nonhuman primate; novel strategies; research study; screening; social cognition

One of the most important functional specializations of the human cerebral cortex is that of the perisylvian cortex and the other subcortical regions with which it is connected. These regions are involved in human higher cognition and behavior, including language. Surprisingly little is known about the biological processes that underlie the development of perisylvian cortical regions in humans, their asymmetry, and presence in other potential model organisms. This proposal is an extension of the Pi's Merit Award, in which we have worked successfully to identify key genes involved in human higher cognition by virtue of their asymmetric expression or enrichment in perisylvian cortex, including CNTNAP2 and other extracellular adhesion molecules that are also related to neuropsychlatric disease. In parallel, we have developed an entirely novel approach to elucidate the complex structure of the transcriptome, and successfully applied this to adult human brain. We propose to apply these methods in conjunction with NextGen sequencing to perform digital gene expression in anatomically defined interconnected human language cortex and its homologues in nonhuman primates. This work will put gene products in a clear functional context, enabling characterization of the set of genes most central to this aspect of human brain organization, rather than relying on less structured means of prioritizing genes for follow-up. Putative differentially expressed genes and key hub genes within the networks will be confirmed using qRT-PCR and In Situ hybridization. Cross species comparisons, in mice and non-human primate species will continue to be performed to investigate the evolutionary conservation of genes that are central hubs of the modules that are enriched in languagerelated cortex in adults, or asymmetrically expressed in the developing human cerebral cortex. This will provide insight into the potential role of these genes in the development and evolution of language and related human cognitive specializations and the relationship of these regions in lower species to homologous human structures. All of this will clearly inform the study of human neurodevelopmental disorders that are related to speech and language, such as autism or schizoprenia, as we and others have already demonstrated, and provide proper context for the use of animal models for these disorders.

人类大脑皮层最重要的功能特化之一是大脑外侧裂 皮质和与之相连的其他皮质下区域。这些区域参与了人类 更高的认知和行为，包括语言。令人惊讶的是， 人类大脑外侧裂周皮质区发育的基础，它们的不对称性， 其他潜在的模式生物。这项提案是Pi的优异奖的延伸，我们在其中 成功地确定了参与人类高级认知的关键基因， 在侧裂周皮质中表达或富集，包括CNTNAP 2和其他细胞外粘附 这些分子也与神经精神疾病有关。与此同时，我们开发了一种全新的 方法来阐明转录组的复杂结构，并成功地将其应用于成人 人脑我们建议将这些方法与NextGen测序相结合， 解剖学定义的人类语言皮层及其同源物在非人类中的基因表达 灵长类动物这项工作将把基因产物放在一个明确的功能背景下，使基因产物的特征化成为可能。 这组基因对人类大脑组织的这一方面最重要，而不是依赖于更少的 结构化的方法，优先考虑后续的基因。推定的差异表达基因和关键枢纽 将使用qRT-PCR和原位杂交确认网络内的基因。跨物种 将继续在小鼠和非人灵长类动物中进行比较，以研究 基因的进化保守性，这些基因是丰富语言相关模块的中心枢纽， 在成年人的大脑皮层中，或在发育中的人类大脑皮层中不对称表达。这将 深入了解这些基因在语言发展和进化中的潜在作用， 相关的人类认知专业化和这些地区的关系，在较低的物种同源 人类结构。所有这些都将清楚地为人类神经发育障碍的研究提供信息， 与言语和语言有关，如自闭症或自闭症，正如我们和其他人已经知道的那样， 证明，并为这些疾病的动物模型的使用提供适当的背景。